This is the competitive renewal application for the Emory Conte Center for the Neurobiology of Mental Disorders (CCNMD) in the Department of Psychiatry and Behavioral Sciences (DPBS) at the Emory University School of Medicine. The goal of this research plan is to utilize state of the art methods ranging from molecular biology to cognitive neuroscience and functional brain imaging to characterize the neurobiological mechanisms by which adverse early life stress (ELS, eg., childhood sexual or physical abuse), increases an individuals' vulnerability to depression and related disorders. Our data suggests that the pathophysiology of major depression in patients with a history of ELS is distinct from that observed in patients with major depression without ELS. Such findings have major implications for nosology, neurochemical pathology and treatment of patients with these disorders. Supported by 4 cores (Administrative, Rat, Assay and Primate), nine projects seek to further characterize the long term neurobiological consequences of ELS in rodents, non-human primates and humans. Using rat and rhesus monkey models of ELS and patients with major depression or social anxiety disorder (SAD) with or without ELS, we focus on alterations in CNS neuroregulators 0001, Paul Plotsky, PhD, PI and immune system dysfunction 0009, Andrew Miller, MD, PI. Michael Davis, PhD, PI utilizes a novel model of learned safety to scrutinize our non-human primate and human patients to further elucidate the long-term behavioral consequences of ELS. The role of ELS in cognitive dysfunction of depression is the focus of 0010, in non-human primates (Stuart Zola, PhD, PI) and also an important component of 0007 (Clinical Psychobiology, Charles Nemeroff, MD, PhD, PI). The latter project also will determine whether men with depression and ELS exhibit the same neuroendocrine and autonomic alterations observed in women, whether patients with SAD and ELS exhibit similar or different neurobiological alterations as patients with major depression and ELS, and will better define the vulnerable periods in development and type of early ELS that contribute to the observed CNS alterations. 0012 (Helen Mayberg, MD and Gregory Berns, MD, PhD, PI) and 0013 (Clinton Kilts, PhD and Xiaoping Hu, PhD) use state-of-the-art functional imaging modalities (PET, fMRI) and diffusion tensor imaging to determine the contribution of ELS to the depression-associated alterations in regional CNS activity, as well as to assess alterations in structural and anatomical connectivity. Finally, 0011 (Zachary Stowe, MD, PI) utilizes a unique clinical population, maternal depression during pregnancy and in the postpartum period, as a novel paradigm to study the consequences of ELS in their offspring. The results of these studies will provide novel data that will likely impact upon pathophysiological subtyping of depression, understanding the neurobiology of risk factors, as well as translating into predictors of treatment response and novel treatment strategies.